KR20000029190A - Process and Intermediates for Preparing Nicotinamide Derivatives - Google Patents

Abstract

PURPOSE: A preparation method of nicotinamide compounds and intermediates thereof are provided which are effective for the manufacture of N-substituted nicotinamide derivatives useful as an antidepressant. CONSTITUTION: Nicotinamide compounds of the general formula(5) is prepared by there action of a compound of the general formula (4) with a base in the presence of an alcoholic solvent in which the compound (4) is prepared by the reaction of a compound of the general formula (3) with a methyl Grignard reagent in the presence of an inactive solvent. In formula, R is C1-C2 alkyl. The compounds are selective inhibitors of calcium-independent phosphodiesterase and useful as antidepressants.

Description

Process and Intermediates for Preparing Nicotinamide Derivatives {Process and Intermediates for Preparing Nicotinamide Derivatives}

The present invention relates to a process for preparing nicotinamide derivatives and to intermediates. Nicotinamide derivatives prepared according to the present invention are described in U.S. Patent No. 4,861,891, filed August 31,1988, "Antidepressant-N-substituted Nicotinamide Compounds" and PCT Application No. PCT / IB9800315 (March 10, 1998). , "Nicotinamide Derivatives". The entirety of each of these US patents and PCT international applications is incorporated herein by reference.

The compounds and methods of the present invention are useful for the preparation of N-substituted nicotinamide derivatives which are selective inhibitors of calcium dependent phosphodiesterases and useful as antidepressants. Such nicotinamide derivatives are selective inhibitors of phosphodiesterase type 4 (PDE 4) and tumor necrosis factor (TNF) production.

The present invention relates to a process for preparing a compound of formula (5) comprising reacting a compound of formula (4) with a base in an alcoholic solvent.

<Formula 5>

<Formula 4>

In a further aspect of the invention, the compound of formula 4 is prepared by reacting a compound of formula 3 with an alkyl Grignard reagent in an inert solvent.

<Formula 3>

Wherein R is (C ₁ -C ₆ ) alkyl.

In a further aspect of the invention, the compound of formula 3 is prepared by reacting a compound of formula 2 with trifluoroacetic anhydride in the presence of an amine base in a chlorinated solvent.

Wherein R is (C ₁ -C ₆ ) alkyl.

In a further aspect of the invention, the compound of formula 2 is prepared by reacting a compound of formula 1 with an alcohol in an acidic medium to form an ester.

When preparing the compound of formula 1, an excess of Grignard reagent is preferably used. Examples of suitable Grignard reagents are methylmagnesium chloride, methylmagnesium bromide and methylmagnesium iodide. Preferably the Grignard reagent is methylmagnesium chloride. The solvent is inert under the reaction conditions, preferably tetrahydrofuran. The base is carbonate, preferably potassium carbonate in methyl alcohol solvent. The esterifying agents are acetic anhydride and amines, preferably trifluoroacetic anhydride and trimethyl amine in dichloroethylene. The ester former is methyl alcohol in hydrochloric acid.

The invention also relates to novel compounds of the formula

<Formula 3>

Wherein R is (C ₁ -C ₆ ) alkyl.

The present invention also relates to novel compounds of formula (4).

<Formula 4>

These novel compounds are intermediates to N-substituted nicotinamide derivatives useful as selective inhibitors of calcium dependent phosphodiesterases and selective inhibitors of phosphodiesterase type 4 (PDE4) and tumor necrosis factor (TNF) production. It is used in the preparation of intermediates for nicotinamide derivatives which are useful as.

The novel synthesis method is shown in Scheme 1 below.

The aminomethyl benzoic acid compound (1) is treated with alcohol in an acidic medium to convert its acid functional groups to obtain an ester compound (2). Trifluoroacetamide ester compound (3) is obtained using acetamide group to protect the free amine of compound (2). Trifluoroacetamide ester compound (3) is treated with methyl Grignard reagent in an inert solvent to give the desired tertiary alcohol compound (4). The acetamide compound (4) is reacted with a carbonate base in an alcoholic solvent to deprotect the trifluoroacetamide to afford the desired amino alcohol compound (5).

The synthesis of the preceding compound (5) was dependent on the optional methyl Grignard addition to 4-cyanobenzoic acid methyl ester (PCT / IB9800315). This methyl Grignard addition needed to be purified by chromatography to provide a complex reaction mixture. The process of the invention produces large amounts of the desired amino alcohol without the need for tedious purification.

Compound (5) is 2-aryloxy-nicotinic acid as disclosed in US Pat. No. 4,861,891 to form nicotinamide derivatives that are selective inhibitors of phosphodiesterase type 4 (PDE4) and tumor necrosis factor (TNF) production. It can be used as an intermediate with the compound.

Useful inhibitors of these PDE4 and TNF can be administered in various dosage forms.

For administration to a person in the treatment or prophylaxis of an inflammatory disease, the oral dose of the compound of formula 1 or a pharmaceutically acceptable salt thereof (active compound) is in single or divided doses for the average adult patient (70 kg) It will generally range from 0.1 to 1000 mg per day. The active compound may be administered in a single or divided dose. Individual tablets or capsules will generally contain 0.1 to 100 mg of the active ingredient in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration will typically be in the range of 0.1 to 10 mg per single dose, if necessary. For intranasal or inhaled administration, dosages are generally formulated in 0.1 to 1% (w / v) solution. In practice, the physician will determine the actual dosage that will be best suited for the individual patient, which will vary with the age, weight and response of the particular patient. Such dosages are examples of average cases, and of course there may be individual cases where more or less dosage ranges are beneficial, and all such dosages are within the scope of the present invention.

For use in humans, the active compounds of the present invention may be administered alone, but will generally be administered as a mixture with a pharmaceutical diluent or carrier selected with respect to the intended route of administration and standard pharmaceutical practice. For example, the active compounds of the present invention can be administered orally in the form of tablets containing excipients such as starch or lactose, in capsule form alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. can do. The active compounds of the invention can be parenterally injected, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, the compounds of the present invention are best used in the form of sterile aqueous solutions which may contain, for example, enough salt to make the solution isotonic or other substances such as glucose.

In addition, the active compounds of the present invention can be administered externally in the treatment of inflammatory diseases of the skin, which can be carried out using creams, jelly, gels, pastes and ointments according to standard pharmaceutical practice.

Therapeutic compounds may also be administered to mammals other than humans. The dosage administered to a mammal will depend on the species of the animal and the disease or disorder to be treated. The therapeutic compound may be administered to the animal in the form of capsules, bolus, tablets or liquid drunks. The therapeutic compound may also be administered to the animal by injection or as an implant. Such formulations are prepared in conventional manner in accordance with standard veterinary practice. Alternatively, the therapeutic compound may be administered with an animal feed and for this purpose, a concentrated feed additive or premix may be prepared for mixing with a normal animal feed.

The present invention is illustrated by the following examples, but is not limited to the details thereof.

Example 1

4-[(2,2,2-Trifluoro-acetylamino) -methyl] -benzoic acid methyl ester

Three 100 mL flasks equipped with an N ₂ inlet, mechanical stirrer and addition funnel were charged with 5.00 g (24.8 mmol) of 4-aminomethyl-benzoic acid methyl ester hydrochloride in 50 mL of CH ₂ Cl ₂ . 7.3 mL (52.1 mmol) triethylamine was added via syringe and the reaction mixture was cooled to 0 ° C. in an acetone / ice bath. 3.7 mL (26.0 mmol) of trifluoroacetic anhydride was charged into the addition funnel and added dropwise to the reaction over 30 minutes. Exotherm occurred at 3.1 ° C. The ice bath was removed after addition of anhydrous trifluoroacetic acid and the reaction was completed by HPLC (Waters Symmetry C-8, 50:50 CH ₃ CN: buffer pH = 3, 1 mL / min, 254 and 205 nm). I was. The reaction was partitioned between 50 mL of H ₂ O and the layers separated. The aqueous layer was extracted with 2 x 50 mL of CH ₂ Cl ₂ . The organic layers were combined, washed with 1 × 100 mL of brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 5.43 g (84%) of a white solid. 1 H NMR (CDCl ₃ , 400 MHz) d 8.01 (2H, br d, CH), 7.28 (2H, br d, CH), 4.58 (2H, br d, CH ₂ ), 3.90 (3H, s, CH ₃ ) ; 13 C NMR (CDCl ₃ , 100 MHz) d 166.5, 140.8, 130.3, 130.1, 127.7, 52.2, 43.4; IR (KBr, cm-1) 3290, 1723, 1702, 1559, 1438; EA Theory: C 50.58, H 3.86, N 5.36, F 21.82. Actual: melting point 70.6 ℃ -74.4 ℃.

Example 2

2,2,2-Trifluoro-N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -acetamide

Three flame dried 200 ml flasks, equipped with N ₂ inlet, mechanical stirrer and addition funnel, were prepared in 4-[(2,2,2-trifluoro-acetylamino) -methyl] -benzoic acid in 135 ml of THF. 3.37 g (12.9 mmol) of methyl ester were charged. It was cooled to 0 ° C. in an acetone / ice bath. Magnesium chloride (21.5 mL of 3M solution in THF, 64.5 mmol) was charged to the addition funnel and added dropwise to the reaction over 15 minutes. The reaction exothermed to 7.4 ° C. The reaction was allowed to warm to room temperature after the Grignard reagent was added. The reaction was monitored by HPLC (Waters Symmetry C-8, 50:50 CH ₃ CN: Buffer pH = 3, 1 mL / min, 254 and 205 nm) and completed after 3.5 hours. The reaction was then quenched slowly with 3.45 g (64.5 mmol) of NH ₄ Cl in 130 mL of H ₂ O. The aqueous layer was extracted with 2 x 250 mL of EtOAc. The combined organic layers were washed with 1 × 500 mL of brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 3.11 g (92.6%) of a pale oil. 1 H NMR (CDCl ₃ , 400 MHz) d 7.50 (2H, br d, CH), 7.27 (2H, br d, CH), 4.50 (2H, br d, CH ₂ ), 1.57 (3H, s, CH ₃ ) ; 13 C NMR (CDCl ₃ , 100 MHz) d 149.4, 134.1, 127.9, 125.2, 112.4, 72.4, 43.6, 31.8; IR (pure, cm-1) 3300, 3092, 2977, 1707, 1558, 1218; EA Theory: C 55.17, H 5.40, F 21.82, N 5.36.

Example 3

2- (4-Aminomethyl-phenyl) -propan-2-ol

In a 100 mL flask equipped with a stir bar, 2,2,2-trifluoro-N- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -acetamide in 31 mL of MeOH was added. g (11.9 mmol) was charged. To this was added 4.11 g (29.75 mmol) K ₂ CO _{3 in} 9.6 mL H ₂ O. The reaction was stirred at rt. The reaction was monitored by HPLC (Waters Symmetry C-8, 50:50 CH ₃ CN: Buffer pH = 3, 1 mL / min, 254 and 205 nm) and completed after 24 hours. The reaction was worked up by adding 150 mL of CHCl _{3 and} 150 mL of brine. The layers were separated and the aqueous layer was extracted with 3 × 150 mL of 10% MeOH / CH ₂ Cl ₂ . The layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give 1.18 g (60%) of a waxy yellow solid.

Example 4

4- (1-hydroxy-1-methyl-ethyl) -benzyl-ammonium; Benzoate

A 25 mL round bottom flask equipped with a stir bar was charged with 184 mg (1.12 mmol) of 2- (4-aminomethyl-phenyl) -propan-2-ol in 2.7 mL of isopropyl alcohol. 136 mg (1.12 mmol) of benzoic acid were added and the reaction stirred at room temperature. Immediately a solid began to precipitate. After 1 h, the mixture was filtered and the solid washed with additional isopropyl alcohol. 141 mg (44% yield) of a white solid was isolated. The filtrate was stirred overnight at room temperature. 32 mg (10% yield) of the second crop was isolated.

The method of the present invention can be used to prepare N-substituted nicotinamide derivatives which are selective inhibitors of calcium dependent phosphodiesterases and useful as antidepressants. The present invention provides novel intermediates useful for the preparation of such nicotinamide derivatives. These novel intermediates are intermediates to N-substituted nicotinamide derivatives useful as selective inhibitors of calcium dependent phosphodiesterases and selective inhibitors of phosphodiesterase type 4 (PDE4) and tumor necrosis factor (TNF) production. It is used in the preparation of intermediates for nicotinamide derivatives which are useful as.

Claims (15)

A method for preparing a compound of Formula 5, comprising reacting a compound of Formula 4 with a carbonate base in an alcohol solvent. <Formula 5> <Formula 4> The method of claim 1 wherein said carbonate is potassium carbonate. The method of claim 1 wherein the solvent is methyl alcohol. The method of claim 1, wherein the compound of Formula 4 is prepared by reacting a compound of Formula 3 with methyl Grignard reagent in a reaction inert solvent. <Formula 3> Wherein R is (C ₁ -C ₆ ) alkyl. The method of claim 4, wherein at least about 5 equivalents of Grignard reagent is used. The method of claim 4, wherein the Grignard reagent is methylmagnesium chloride. The method of claim 4, wherein the solvent is tetrahydrofuran. The method of claim 4, wherein the compound of Formula 3 is prepared by reacting a compound of Formula 2 with acetic anhydride and an amine base in a chlorinated solvent. <Formula 2> Wherein R is (C ₁ -C ₆ ) alkyl. The method of claim 8, wherein the acetic anhydride is trifluoroacetic anhydride. The method of claim 8, wherein the amine is triethylamine. The method of claim 8, wherein the solvent is dichloroethylene. The method of claim 8, wherein the compound of Formula 2 is prepared by reacting a compound of Formula 1 with an alcohol in an acidic medium to form an ester group. <Formula 1> 13. The method of claim 12, wherein said ester former is methyl alcohol in hydrochloric acid. A compound of formula <Formula 3> Wherein R is (C ₁ -C ₆ ) alkyl. A compound of formula <Formula 4>